Methods and compositions for the inhibition of cathepsins

Abstract

Methods and compositions for modulating cell death by contacting a cell with an Spi2A polypeptide or an Spi2A polypeptide equivalent are disclosed. In addition, methods of treating a subject by providing the subject a composition that includes an Spi2A polypeptide or an Spi2A polypeptide equivalent are disclosed. The Spi2A polypeptide and Spi2A polypeptide equivalent can be delivered to the subject using gene therapy techniques. The subject can be a patient with a disease associated with an abnormal rate of cell death, such as septic shock or myocardial infarction. Also disclosed are methods of preparing and storing donor granulocytes, involving contacting the donor granulocytes with an Spi2A polypeptide or an Spi2A polypeptide equivalent.

1 . A method for modulating cell death in a cell comprising contacting said cell with an Spi2A polypeptide or an Spi2A polypeptide equivalent.  
     
     
         2 . The method of  claim 1 , wherein the cell is contacted with an Spi2A polypeptide.  
     
     
         3 . The method of  claim 1 , wherein the cell is contacted with an Spi2A polypeptide equivalent.  
     
     
         4 . The method of  claim 3 , wherein the Spi2A polypeptide equivalent is a polypeptide from Serpin B1, Serpin B2, Serpin B3, Serpin B4, Serpin B6, Serpin B8, or Serpin B9.  
     
     
         5 . The method of  claim 4 , wherein the Spi2A polypeptide equivalent is a polypeptide from Serpin B9.  
     
     
         6 . The method of  claim 1 , wherein the Spi2A polypeptide or Spi2A polypeptide equivalent is a polypeptide comprising 4 to 8 consecutive amino acid residues of the amino acid sequences MAGVGCCA or FVVAECCM.  
     
     
         7 - 11 . (Canceled)  
     
     
         12 . The method of  claim 1 , further defined as a method of modulating apoptosis.  
     
     
         13 . The method of  claim 1 , wherein said cell is a T lymphocyte.  
     
     
         14 . The method of  claim 12 , wherein said method is further defined as a method for facilitating the differentiation of said lymphocyte into a memory T lymphocyte.  
     
     
         15 . The method of  claim 14 , further defined as a method of promoting the development of an immune response in a subject against a target cell.  
     
     
         16 . The method of  claim 1 , wherein the Spi2A polypeptide or Spi2A polypeptide equivalent is comprised in a vaccine.  
     
     
         17 . The method of  claim 15 , wherein the target cell is a tumor cell or a cell that is infected by a pathogen.  
     
     
         18 - 20 . (Canceled)  
     
     
         21 . The method of  claim 12 , wherein said apoptosis is apoptosis due to increased lysosomal permeability in said cell.  
     
     
         22 . The method of  claim 21 , wherein said increased lysosomal permeability results in release of at least one lysosomal protease within said cell.  
     
     
         23 . The method of  claim 22 , wherein said lysosomal protease is a cysteine protease.  
     
     
         24 . (Canceled)  
     
     
         25 . The method of  claim 1 , further defined as a method of modulating autophagic cell death.  
     
     
         26 . The method of  claim 1 , further defined as a method of modulating TNF-α-mediated cell death.  
     
     
         27 . The method of  claim 1 , further defined as a method of modulating cell death due to reactive oxygen species within said cell.  
     
     
         28 . The method of  claim 1 , further defined as a method of modulating cell death due to necrosis.  
     
     
         29 . The method of  claim 1 , wherein said cell is in a subject.  
     
     
         30 . The method of  claim 29 , wherein said subject is a human.  
     
     
         31 . The method of  claim 30 , wherein said human is a patient with an infection.  
     
     
         32 . (Canceled)  
     
     
         33 . The method of  claim 31 , wherein the infection is an infection due to a biological weapon.  
     
     
         34 . (Canceled)  
     
     
         35 . The method of  claim 30 , wherein said human is a patient with septic shock.  
     
     
         36 . The method of  claim 30 , wherein said human is a patient with hepatic failure.  
     
     
         37 . The method of  claim 36 , wherein the hepatic failure is fulminating hepatic failure.  
     
     
         38 . (Canceled)  
     
     
         39 . The method of  claim 30 , wherein said human is a patient with an inflammatory disease.  
     
     
         40 . The method of  claim 39 , wherein the inflammatory disease is liver disease.  
     
     
         41 - 45 . (Canceled)  
     
     
         46 . The method of  claim 30 , wherein said human is a patient with vascular disease.  
     
     
         47 - 48 . (Canceled)  
     
     
         49 . The method of  claim 46 , wherein said vascular disease is a myocardial infarction.  
     
     
         50 . The method of  claim 30 , wherein said human is a patient with cancer.  
     
     
         51 . The method of  claim 30 , wherein said human is a patient with a bone disease.  
     
     
         52 . The method of  claim 51 , wherein the bone disease is osteoporosis.  
     
     
         53 - 55 . (Canceled)  
     
     
         56 . The method of  claim 30 , wherein said human is a patient with a viral infection.  
     
     
         57 - 58 . (Canceled)  
     
     
         59 . The method of claim  58 , wherein said immune disorder is an autoimmune disorder.  
     
     
         60 . (Canceled)  
     
     
         61 . The method of  claim 30 , wherein said human is a patient with multiple sclerosis.  
     
     
         62 . (Canceled)  
     
     
         63 . The method of  claim 30 , wherein said human is a patient with arthritis.  
     
     
         64 . The method of  claim 63 , wherein said patient with arthritis is a patient with rheumatoid arthritis.  
     
     
         65 - 90 . (Canceled)  
     
     
         91 . A method of treating a subject comprising: 
 (a) providing a composition comprising: 
 (1) an Spi2A polypeptide or an Spi2A polypeptide equivalent; and  
 (2) a pharmaceutical preparation suitable for delivery to said subject; and  
   (b) administering said composition to said subject.    
     
     
         92 - 187 . (Canceled)  
     
     
         188 . A method of preparing donor granulocytes for storage, comprising: 
 (a) obtaining donor granulocytes from a suitable donor;    (b) isolating said donor granulocytoes;    (c) contacting said donor granulocytes with a composition comprising an Spi2A polypeptide or an Spi2A polypeptide equivalent and a pharmaceutical preparation suitable for delivery of said donor granulocytes; and    (d) storing said donor granulocytes.    
     
     
         189 . The method of  claim 188 , further comprising treatment of the donor with C-GSF prior to obtaining granulocytes from the donor.  
     
     
         190 . The method of  claim 189 , further comprising purifying the granulocytes by leukapheresis following isolation of the granulocytes.  
     
     
         191 . The method of  claim 188 , wherein said composition comprises an Spi2A polypeptide.  
     
     
         192 . The method of  claim 188 , wherein said composition comprises an Spi2A polypeptide equivalent.  
     
     
         193 . The method of  claim 188 , wherein the Spi2A polypeptide or Spi2A polypeptide equivalent is a polypeptide comprising 4 to 8 consecutive amino acid residues of the amino acid sequences MAGVGCCA or FVVAECCM.  
     
     
         194 - 198 . (Canceled)  
     
     
         199 . The method of  claim 192 , wherein the Spi2A polypeptide equivalent is a polypeptide from Serpin B1, Serpin B2, Serpin B3, Serpin B4, Serpin B6, Serpin B8, or Serpin B9.  
     
     
         200 . The method of  claim 199 , wherein the Spi2A polypeptide equivalent is a polypeptide from Serpin B9.  
     
     
         201 . The method of  claim 188 , wherein said method of storing donor granulocytes results in reduction of apoptosis of said donor granulocytes.  
     
     
         202 - 204 . (Canceled)